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乳腺癌患者血清中肿瘤抑制基因启动子的高甲基化

Tumor suppressor gene promoter hypermethylation in serum of breast cancer patients.

作者信息

Dulaimi Essel, Hillinck Jeanne, Ibanez de Caceres Inmaculada, Al-Saleem Tahseen, Cairns Paul

机构信息

Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.

出版信息

Clin Cancer Res. 2004 Sep 15;10(18 Pt 1):6189-93. doi: 10.1158/1078-0432.CCR-04-0597.

Abstract

PURPOSE

Breast cancer is the most common malignancy in American women and the second leading cause of death from cancer. The genetic and epigenetic alterations that initiate and drive cancer can be used as targets for detection of neoplasia in bodily fluids. Tumor cell-specific aberrant promoter hypermethylation can be detected in nipple aspirate and ductal lavage from breast cancer patients. In this study, we examine serum, a more readily accessible bodily fluid known to contain neoplastic DNA from individuals with cancer, for methylation-based detection of breast neoplasia.

EXPERIMENTAL DESIGN

We examined the promoter methylation status of three normally unmethylated biologically significant cancer genes, RAS association domain family protein 1A (RASSF1A), adenomatous polyposis coli (APC), and death-associated protein kinase (DAP-kinase), by sensitive methylation-specific PCR in 34 breast tumor and paired preoperative serum DNA. The 34 patients comprised 7 ductal carcinoma in situ (CIS), 3 lobular CIS, 5 stage I and 15 stage II to IV invasive ductal carcinomas, and 4 invasive lobular carcinomas. Normal and benign tissue and serum control DNA were also examined to determine the specificity of hypermethylation.

RESULTS

Hypermethylation of one or more genes was found in 32 of 34 (94%) breast tumor DNA. APC was hypermethylated in 15 of 34 (47%), RASSF1A in 22 of 34 (65%), and DAP-kinase in 17 of 34 (50%) tumors. Twenty-six (76%) of the corresponding serum DNA were positive for promoter hypermethylation, including ductal CIS, lobular CIS, stage I disease, and lobular carcinoma patients. No hypermethylation of APC, RASSF1A, or DAP-kinase was observed in serum DNA from normal healthy women and patients with inflammatory breast disease or nonneoplastic breast tissue specimens. A gene unmethylated in the tumor DNA was always found to be unmethylated in the matched serum DNA (100% specificity).

CONCLUSIONS

Tumor cell specific promoter hypermethylation of APC, RASSF1A, and DAP-kinase is present in ductal CIS, lobular CIS, and all grades and stages of invasive breast cancer. Hypermethylation can be detected by methylation-specific PCR analysis in serum DNA from patients with preinvasive and early-stage breast cancer amenable to cure. If confirmed in additional studies, hypermethylation-based screening of serum, a readily accessible bodily fluid, may enhance early detection of breast cancer.

摘要

目的

乳腺癌是美国女性中最常见的恶性肿瘤,也是癌症死亡的第二大主要原因。引发和推动癌症的基因及表观遗传改变可作为体液中肿瘤形成检测的靶点。在乳腺癌患者的乳头抽吸液和导管灌洗液中可检测到肿瘤细胞特异性的异常启动子高甲基化。在本研究中,我们检测血清(一种更容易获取的体液,已知含有癌症患者的肿瘤性DNA),以基于甲基化检测乳腺肿瘤。

实验设计

我们通过敏感的甲基化特异性PCR检测了34例乳腺肿瘤及配对的术前血清DNA中三个正常情况下未甲基化的具有生物学意义的癌症基因,即RAS关联结构域家族蛋白1A(RASSF1A)、腺瘤性息肉病基因(APC)和死亡相关蛋白激酶(DAP-激酶)的启动子甲基化状态。34例患者包括7例导管原位癌(CIS)、3例小叶原位癌、5例I期和15例II至IV期浸润性导管癌以及4例浸润性小叶癌。还检测了正常和良性组织及血清对照DNA,以确定高甲基化的特异性。

结果

在34例乳腺肿瘤DNA中的32例(94%)发现一个或多个基因的高甲基化。34例肿瘤中,15例(47%)的APC高甲基化,22例(65%)的RASSF1A高甲基化,17例(50%)的DAP-激酶高甲基化。相应血清DNA中有26例(76%)启动子高甲基化呈阳性,包括导管原位癌、小叶原位癌、I期疾病和小叶癌患者。在正常健康女性以及患有炎性乳腺癌或非肿瘤性乳腺组织标本患者的血清DNA中未观察到APC、RASSF1A或DAP-激酶的高甲基化。在肿瘤DNA中未甲基化的基因在匹配的血清DNA中始终未甲基化(特异性为100%)。

结论

APC、RASSF1A和DAP-激酶的肿瘤细胞特异性启动子高甲基化存在于导管原位癌、小叶原位癌以及所有分级和分期的浸润性乳腺癌中。通过甲基化特异性PCR分析可在适合治愈的浸润前和早期乳腺癌患者的血清DNA中检测到高甲基化。如果在更多研究中得到证实,基于甲基化的血清筛查(一种容易获取的体液)可能会提高乳腺癌的早期检测率。

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